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regulation of gpcr signalling Flashcards

be able to write out the pathways n shit here e.g. in an essay

1
Q

what are GPCRs

A

g protein coupled receptors
largest receptor family
can be tissue specific
polypeptide chain of 300-500 amino acids

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2
Q

GPCRs are the largest receptor family with ____ members

A

> 800

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3
Q

approximately 500 GPCRs are expressed in ____ tissues

A

olfactory - sense of smell
(example of tissue specific)

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4
Q

___ to ___% of drugs in the market target GPCRs

A

30 - 50%

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5
Q

what are GPCRs characterised by (4)

A

7 transmembrane domains of alpha helices - largest family of membrane spanning receptors

distinctive structure

extracellular N terminus

intracellular C terminus

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6
Q

what shape does the transmembrane of a GCPR form and what does it contain

A

barrel - contains ligand binding site for ligand to bind to and activate

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7
Q

what are G proteins

A

heterotrimeric proteins of alpha, beta, gamma subunits

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8
Q

what does ligand binding in GPCRs cause

A

conformation change, leading to receptor acting as a guanine nucleotide exchange factor (GEF)

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9
Q

what is the role of GTP in GPCRs

A

GTP activates the G protein and causes dissasociation of the Ga G alpha subunit from the beta gamma subunit

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10
Q

what is the role of guanine nucleotide exchange factor GEF in GPCRs

A

loads G protein with GTP, which activates it

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11
Q

there are distinct Ga subunits that have different signal transduction through second messagers. true or false?

A

true

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12
Q

what is the signal transduction pathway of G alpha s (Gs) / stimulatory G alpha subunit

A

positive effect on adenylate cyclase

inc cyclic AMP (cAMP)

inc activation protein kinase A (PKA)

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13
Q

what is the signal transduction pathway of G alpha i (Gi) / stimulatory G alpha subunit

A

negative effect on adenylate cyclase

dec cyclic AMP (cAMP)

dec protein kinase A (PKA)

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14
Q

what is the signal transduction pathway of G alpha 12/13 (G12/13) / stimulatory G alpha subunit

A

activates Rac/Rho protein (a GTPase protein)

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15
Q

what is the signal transduction pathway of G alpha q (Gq) / stimulatory G alpha subunit

A

interacts with PLC phospholipase C which

converts PIP2= Phosphatidylinositol 4,5-bisphosphate

to IP3 = inositoltriphosphate and
DAG = diacylglycerol

IP3 inc PKC = Protein kinase C

inc Calcium ions leading to

activates CamKII = calmoduline-dependent kinase II

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15
Q

what do second messengers do

A

amplify signal

ie 1 mol activates GPCR, activates 1000 mols, downstream effects to 100,000 mol

e.g. Gi

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15
Q

GPCR signalling is not only determined by agonist binding, but is also ____ ____ by interactions with other receptors

A

allosterically modulated

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15
Q

some GCPRs dimerise when activated - what are these called and what do they mean (2)

A

homodimer - same GCPR
heteromers - different GCPR

type of dimer will impact GPCR signalling downstream

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15
Q

what are bivalent ligands

A

2 bound ligands that activate both GPCR heteromers
(each binds to GPCR, then form dimer, then other binds for third different effect)

aka form new ligand, only activates certain receptors if they are bivalent (stuck together in heterodimer)

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15
Q

receptor dimerisation is common in other types of receptors such as ___ ___ but remains controversial in the GPCR

A

tyrosine kinases

we are beginning to generate ligands that can activate both receptors in a dimer pair e.g. bivalent ligands

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16
Q

risk of cell signalling if not controlled

A

pathogenic signalling causing disease tumourogenisis

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17
Q

example of effect of pathogenic signalling

A

tumourogenisis, cancers

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18
Q

how to avoid pathogenic signalling

A

changing sensitivity of receptors can be adjusted based on levels of stimulation
(GPCR desensitisation)

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19
Q

changing sensitivity of receptors can be adjusted based on levels of stimulation. what is an example of this

A

rhodopsin is a GPCR in the rods of the retina - in very bright and dark light, sensitivity of receptors change - this is GPCR re/desensitising

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20
what is GPCR desensitisation
waning/ reduction of cellular response in the face of continued or repeated stimulation - e.g. light ie agonist response decreases also conserves ATP
21
what is homologous desensitisation
the receptor only becomes desensitised to a specific agonist and normal response returns when a different agonist is used
22
what is heterologous desensitisation
receptor becomes desensitised to any agonist
23
how does activation of GPCRs reduce GPCR activation at a later time (8)
add agonist, activate GPCR GPCR activation activates second messenger systems (e.g. cAMP) including PKA protein kinase kinases phosphorylate proteins e.g. the activated GPCR when the G protein heteromer is dissociated (or coupled to G protein) the newly phosphorylated sites on the GPCR cannot reassociate the G protein heteromer this causes uncoupling of G protein from GPCR the second messenger no longer promotes signal transduction from the receptor as ligand is less bound to GPCR beta arrestin is recruited to replace G protein heteromer, blocks G protein heteromer blocking cell signalling
24
what do protein kinases do
phosphorylate proteins
25
example of a protein kinase
PKA
26
what does beta arrestin do (2)
block G protein heteromer by replacing it and binding to GPCR once it dissociates inhibits downstream signalling transduction when interacts with GCPR aka signalling desensitisation
27
how do we know beta arrestin replaces G protein heteromer
we genetically engineer and attach green fluorescent protein (GFP) to beta arrestin
28
affect on beta-arrestin when receptor agonists e.g. isoproterenol is administered
forms clusters at cell membrane to bind to GPCR- moves away from defuse localisation translocates to membrane shown as fluoresence
29
receptor agonist example
isoproterenol
30
the structure of beta arrestin suggests it is able to interact with proteins such as ___ and ___
clathrin AP2
31
what are clathrin and AP2 involved in
endocytosis of receptors from cell membrane into cell to be altered and resensitised means over time the receptor will gain sensitivity
32
how does clathrin and AP2 work
endocytic these proteins bind and remove receptor from membrane membrane invaginates receptor eventually removed from EC facing environment invagination eventually forms a vesicle containing GCPR - no longer on membrane clathrin coated vesicle eventually uncoats and forms early endosome receptors dephosphorylate and recycle back to cell membrane to signal anew GPCR no longer phosphorylated so G protein can recouple and GPCR is resensitised, transduction can occur
33
what is clathrin (4)
structural molecule complex of light chain and heavy chain/ 2 proteins 3 legged structure/ trimeric self form in cells as a lattice of hexagones, allows to bend membrane/ internalisations
34
what other outcome can occur for an early endosome (5):
downregulation: GCPR as early endosome sent for degradation and broken down results less receptors avaliable for signalling receptor downregulation long term, is why patients/addicts can present with drug tolerance - less receptors so inc dose needed receptor signalling cannot recover when agonist present until new synthesis of receptor occurs
35
what is early endosome degradation caused by
lysosome
36
how does a degraded early endosome recover
receptor signalling cannot recover when agonist present until new synthesis of receptor occurs via transcription/ translation - cannot reuse agonist should be removed also
37
beta arrestin is also a ____ ____
signal transducer - arrestin mediated signalling
38
what can beta arrestin activate
sarcoma (Src) by accumulating clathrin coated vesicles
39
what is sarcoma (Src) used for
activates MAPK MAPkinase signalling pathway - cell growth, proliferation
40
what is the MAPK pathway also known as
Ras-Raf-MEK-ERK pathway (each protein phosphorylates protein that comes after)
41
in the MAPK pathway, what is the function of ERK
translocates to nucleus and trigger transcription and translation
42
what, other than beta arrestin, can activate the MAPK pathway aka is a signal transducing protein unit
G protein beta gamma subunit exact mechanism varies depending on cell type - can activate through Src or directly Ras
43
what can activate the PI-3 Kinase (PI3K) pathway
G protein beta gamma subunit
44
what does the PI-3 Kinase (PI3K) pathway activate
PKB/Akt
45
what does PKB/Akt do
inhibit apoptotic processes, contributing to cellular survival pathways relevant to cancer -- upregulated in cancer
46
what can activate ionotropic channels on cell membrane e.g. calcium ions from EC environment to IC environment or potassium ions from IC to EC
beta gamma subunit
47
what is an ionotrophic channel
undergoes conformational change when activated and allow ions to flow through
48
two ways GPCR signalling originates from
1- G protein signalling response mediated from alpha subunit and beta-gamma subunits 2- beta-arrestin signalling response, can produce distinct pathways not present in G alpha signalling pathways (1st option)
49
what is biased GPCR signalling aka signalling bias
biased agonists can activate one signalling pathway over another (G protein signalling vs beta arresting signalling response)
50
example of biased agonist
oliceridine - opioid med
51
what does oliceridine act as an agonist for and what does it activate
biased agonist for mu opioid receptor preferentially activates G protein signalling over beta arrestin signalling
52
effect of oliceridine in terms of drug tolerance
reduced beta arrestin recruitment less receptor internalisation reduced likelihood of drug tolerance as drug does not go through desensitisation or downregulation common with drugs e.g. morphine that bind to mu opioid receptors
53
what do GCPRs transduce
signal from wide range of extracellular ligands
54
examples of extracellular ligands that GCPRs transduce
light, calcium ions, odorants, small molecules, proteins
55
is the GCPR N terminus intra or extracellular
extracellular
56
is the GCPR C terminus intra or extra cellular
intracellular
57
how are GCPRs activated
ligand binds
58
what is downstream signalling
also known as signal transduction pathways, are the processes that control how cells respond to signals and drive their overall activity
59
what is the most pharmacologically relevant heterotrimeric protein of G proteins
alpha (Ga) is the most pharmacologically relevant
60
what is GEF
guanine nucleotide exchange factor (GEF)
61
how is GTP activated
GEF guanine nucleotide exchange factor displaces GDP and loads on GTP
62
the recruitment of beta arrestin requires
phosphorylation from PKA if PKA null cell, no beta arrestin aka no clusters, diffused expression
63
what is resensitisation
recovery of cell responsiveness via endocytosis after desensitisation then, can be resensitised through dephosphorylation through protein phosphates like PP2A and recycled back to cell membrane
64
When an RTK is activated it will form a dimer with another RTK. It will then ___________ the dimer partner to allow for adaptor proteins to bind.
transphosphorylate
65
Activation of PI3K by RTKs results in downstream signaling which activates which protein?
PKB
66
Receptor downregulation can be overcome by ______________.
Removing agonist and allowing new synthesis
67
class A GPCRs
interact with ligands in the EC
68
class B GPCRs
interact with peptides
69
class C GPCRs
are dimers
70
subunit G ____ allows for drug receptor complex specificity
alpha as it is variable
71
what occurs in the intracellular C terminus when the GPCR binds
undergoes conformational change causing high affinity to the G protein
72
what anchors the GPCR
the beta gamma subunit
73
how else can amplification occur
freed active receptors can bind to other G proteins
74
cholera toxin
activates Gs singalling pathway via ADP-ribosylation of Gas subunit dissociates Gas subunit from beta gamma subunit activates adenylyl cyclase inc cAMP excessively inc PKA phosphorylates/ opens ions channels in intestinal epithelium inc flow of ions into intestine lumen osmosis into lumen profuse diarrhoea/ dehydration aka cholera
75
carvediol
beta-adrenergic receptor blocker signalling bias for beta-arrestin mediated signalling clinically used for treating chronic heart failure
76
what is the difference between desensitisation and downregulation
desensitisation is a temporary reduction while downregulation is a long term decrease desensitisation prevents overstimulation due to excessive signalling and loss of energy downregulation leads to inc tolerance
77
what is a GRK
G-protein-coupled receptor kinase phosphorylate activated GPCRs, marking for desensitisation
78
what two factors contribute to desensitisation
GRKs - account for some reduced signalling as leads to reduced interaction with G-protein β-arrestin recruitment - accounts for most of desensitisation as outcompetes G-proteins
79
how were β-arrestins discovered
it was seen that β-arrestins prevented coupling of phosphorylated rhodopsin to the G-protein transducin proved that β-arrestins do not readily dissociate, but G-proteins do
80
β-arrestin mutations
β-arrestins can be mutated to engage only one receptor site, leaving the other free to bind with the G protein, resulting in simoultaneous interaction
81
what type of desensitisation does salbutamol cause
homologous B2 adrenergic receptor post exposure to salbutamol agonist
82
where do clathrin and AP2 bind
C termini
83
β-Adrenergic Agonists (e.g. albuterol) and dopamine agonists (e.g. fenoldopam) use which G pathway, and what effects result
stimulate G alpha albuterol - inc cAMP leads to inc bronchodilation, good for asthma treatment fenoldopam - inc cAMP, inc vasodilation, dec blood pressure
84
Morphine uses which G pathway, and what effects result - check pls lol
stimulates G inhibitory dec cAMP dec neuronal activity analgesic effect
85
Currently, there are limited therapeutic agents that specifically target the ___ pathway. However, research is ongoing to develop modulators that can influence this pathway for potential therapeutic benefits.
G 12/13

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